Patent GB-811959-A (GB)
Title: New phenthiazine derivatives and their preparation
IPC: C07D417/06
Filed: 1957-03-26
Abstract: The invention comprises phenothiazine derivatives of the general formula (I) <FORM:0811959/IV (b)/1> and their acid addition and quaternary ammonium salts (wherein X is a sulphur atom or SO group, R1 and R2 are each an alkyl group containing not more than five carbon atoms or one of R1 and R2 is hydrogen and the other is an alkyl group as above, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic group, e.g. pyrrolidino, piperidino, morpholino, piperazino, or 4-alkyl-, 4-hydroxyalkyl- or 4-acyloxyalkylpiperazino, and B is a straight or branched divalent aliphatic hydrocarbon group containing two to five carbon atoms, unsubstituted or substituted by <FORM:0811959/IV (b)/2> wherein A is a single bond or methylene group) and their preparation by known methods for the preparation of 10-aminoalkylphenothiazines.  For therapeutic purposes the bases of general formula (I) are preferably converted into acid addition salts and quaternary ammonium derivatives with, respectively, acids and halides having pharmaceutically acceptable anions, examples of which are supplied. Examples describe the preparation of 3-methanesulphonyl - 10 - (3 - dimethylaminopropyl)-, (3-dimethylamino - 2 - methylpropyl) -, (3 - pyrrolidino - 2 - methylpropyl) -, (3 - 41 - methyl-11 - piperazinyl - 2 - methylpropyl) -, (3 - 41-methyl - 11 - piperazinylpropyl) - and (3 - pyrrolidinopropyl)-phenothiazine from 3-methanesulphonylphenothiazine and the appropriate tertiary - aminoalkyl halides; 3 - methanesulphonyl - 10 - (2 - dimethylaminopropyl) and (2:3 - bis - dimethylaminopropyl) - phenothiazine by thermal decarboxylation of 3-dimethylamino-2-propyl and 1:3-bis-dimethylamino - 2 - propyl - 3 - methanesulphonylphenothiazine - 10 - carboxylate respectively; 3-methanesulphonyl - 10 - (3 - piperidinopropyl), (3 - diethylaminopropyl) -, (3 - 41 - hydroxyethyl - 11 - piperazinylpropyl) - and (3 - methylaminopropyl) - phenothiazine by reacting 3-methanesulphonyl - 10 - (3 - toluene - p - sulphonyloxypropyl) - phenothiazine with the appropriate amine; 3 - methanesulphonyl - 10-(3 - 41 - acetoxyethyl - 11 - piperazinylpropyl)-phenothiazine by acetylating the corresponding hydroxy compound; 3-methanesulphonyl-10-(3 - dimethylaminopropyl) - phenothiazine by reductive methylation of the corresponding primary amine; 3-methanesulphonyl-10-(3-dimethylaminopropyl) phenothiazine by the cyclisation of 2-bromo-21-(3-dimethylaminopropylamino) - 41 - methanesulphonyldiphenyl sulphide, and 3 - methanesulphonyl - 9 - oxy - 10-(3 - dimethylamino - 2 - methylpropyl) - phenothiazine by the oxidation of the corresponding phenothiazine.  Hydrochlorides, fumarates, oxalates, methanesulphonates, maleates and picrates of some of these compounds are also described.  3 - Methanesulphonylphenothiazine is obtained (with the 1-isomer) by the action of sulphur in the presence of iodine on 3-methanesulphonyldiphenylamine, prepared by decarboxylating 2 - carboxy - 31 - methanesulphonyldiphenylamine.  3 - Dimethylamino - 2 - propyl 3 - methanesulphonylphenothiazine - 10 - carboxylate (and its hydrochloride) are prepared from 1-dimethylaminopropan - 2 - ol and 3 - methanesulphonylphenothiazine - 10 - carbonyl chloride, obtained in turn by the action of phosgene on 3-methanesulphonylphenothiazine; 1:3 - bis - dimethylamino - 2 - propyl 3 - methanesulphonylphenothiazine - 10 - carboxylate is prepared similarly from 1:3-bis-dimethylaminopropan-2-ol.  3 - Methanesulphonyl - 10 - (3 - toluene - p-sulphonyloxypropyl) pehnothiazine is prepared by condensing p - toluenesulphonyl chloride with 3 - methanesulphonyl - 10 - (3 - hydroxypropyl) phenothiazine, prepared by acid hydrolysis of 3 - methanesulphonyl - 10 - (3-tetrahydropyranyloxy) phenothiazine obtained in turn by condensing 3-tetrahydropyranyloxy-1-chloropropane with 3-methanesulphonylphenothiazine.  3 - Methanesulphonyl - 10 - (3 - aminopropyl)-phenothiazine is prepared by treating 3-methanesulphonyl - 10 - (3 - toluene - p - sulphonyloxypropyl) phenothiazine with ammonia.  2 - Bromo - 21 - (3 - dimethylaminopropylamino) - 41 - methanesulphonyldiphenyl sulphide is obtained by condensing 1-dimethylamino - 3 - chloropropane with 2 - bromo - 21-amino - 41 - methanesulphonyldiphenyl sulphide.